Method of Treating Bone Pain Caused by Osteoarthritis

ABSTRACT

A method of treating bone pain caused by osteoarthritis by administering to a patient an effective amount of a composition containing a bone edema medication, such as a vasoactive medication or phosphodiesterase inhibitor, including a PDE-5 inhibitor.

FIELD OF THE INVENTION

The present invention generally relates to the fields of orthopedics andrheumatology and, in particular, to a treatment for bone pain associatedwith osteoarthritis and related conditions. More specifically, thepresent invention relates to a method of treating pain caused byosteoarthritis with bone edema medications. Medications that may be usedaccording to the present invention include vasoactive medications, suchas phosphodiesterase inhibitors, which modulate blood flow to bone of apatient in the vicinity of an arthritic joint to affect the physiologyof the bone in a manner that leads to a reduction in the pain associatedwith osteoarthritis.

BACKGROUND OF THE INVENTION

Osteoarthritis is the most common musculoskeletal and joint diseases inthe world. Because medical advances have increased the average lifespan,yet have not devised an effective means of preventing wear and tear ofthe joints, osteoarthritis is rapidly becoming a significant medical andfinancial burden to the world (Pelletier et al. 2006) and is a leadingcause of impaired mobility in the elderly. (Felson 2006). Osteoarthritisis a condition of primary failure of articular cartilage, which isaccompanied by subchondral hardening of bone, osteophytes (bone spurs)at the joint margin, juxtaarticular bone cysts, and joint spacenarrowing. Pain is the most prominent and disabling symptom ofosteoarthritis. (Felson 2005). Osteoarthritis usually develops in thesmaller joints of the fingers, the weight-bearing joints of the leg, andthe movable portions of the spine, although any diarthrodial joint canbe affected.

Osteoarthritis was long thought to reflect the aging process, in whichrepetitive use of joints results in cartilage erosion. And whereas it istrue that osteoarthritis is characterized by cartilage loss, cartilagedamage cannot be the source of the pain, as there are no pain fibers inarticular cartilage, and in some patients cartilage loss may occurwithout any accompanying symptoms. (Felson 2005). As more is understoodabout the molecular structure and function of cartilage, the painassociated with osteoarthritis appears to be the result of a complexinterplay between mechanical, cellular, and biochemical forces.

At present, there are no means to effectively restore damaged articularcartilage to its healthy state, i.e., once damaged, human adultcartilage remains damaged for life. Thus, the primary goals of treatmentof osteoarthritis are to help patients understand their disease, relievetheir pain, minimize their disability, and limit the progression oftheir disease. Medical treatment of osteoarthritis often involvesadministration of pain relievers such as acetaminophen or aspirin.Alternatively, nonsteriodal anti-inflammatory drugs (NSAIDs), such asibuprofen, nabumetone or naproxen, amongst others, may be administered.Although these drugs act to “block” the pain and/or reduce inflammation,they do not affect the physiology underscoring and producing the pain.Such an approach is suggested by the instant invention.

Articular cartilage itself is relatively avascular, and lacks painreceptors. Thus, although osteoarthritis represents a failure ofcartilage, the pain cannot and does not originate from the damagedcartilage itself. Rather, the pain can be mediated by the onlyperi-articular structures which possess the neural apparatus for sensingpain (i.e., nociceptors): namely, the synovium and the bone underlyingthe cartilage. It is only those structures (alone or in combination)that can be responsible for the sensation of pain experienced bypatients suffering from osteoarthritis.

There is clinical evidence suggesting that pressure within the bone maycontribute, at least in part, to joint pain. For example, the medicalliterature has discussed a case in which Dr. Scott Dye of San Franciscoinjected his own bone with saline under pressure, in the name ofscience. He experienced pain which lasted for a year.

Also, more than 30 years ago, it was observed that pain due to severeosteoarthritis may be associated with “intraosseous hypertension,” i.e.,pressure within the bone. (Arnoldi et al. 1975). Intraosseoushypertension is the manifestation of edema within the bone. Thus, it hasbeen proposed that local vascular changes may be important in thepathogenesis of degenerative arthritis and the production of itsassociated symptoms. (Arnoldi et al. 1972). It has been further observedthat surgical decompression of bone (specifically in the case ofosteonecrosis) can relieve bone pain. Use of surgery, however, toalleviate pressure within the bone is not ideal. For one thing, surgerycan produce myriad side effects and complications, but more to thepoint, the problem with surgical decompression is that its benefit willbe transient. The fenestrations created during so-called decompressiveprocedures are bound to fill with fibrocartilage. Thus, there is anongoing need for a safe and effective method for alleviating pressure inbone causing joint pain, most typically found in patients suffering fromosteoarthritis.

SUMMARY OF THE INVENTION

It is an object of this invention to provide a method of treating painassociated with osteoarthritis. It is another object of this inventionto provide a method of treating intraosseous hypertension associatedwith osteoarthritis. It is a further object of this invention to providea method of treating osteoarthritis. The present invention includes amethod of treating bone pain associated with osteoarthritis and otherconditions by administering to a patient a therapeutically effectiveamount of a pharmaceutically acceptable bone edema medication. Boneedema medications used according to the present invention includevasoactive medications such as phosphodiesterase inhibitors. Accordingto an aspect of the present invention, a therapeutically effectiveamount of a subtype 5 phosphodiesterase enzyme (PDE5) selectiveinhibitor, such as avanafil, sildenafil, tadalafil, udenafil, vardenafiland zaprinast, may be administered. The medication is administered in anamount sufficient to reduce pain associated with osteoarthritis and maybe administered, for example, via intravenous, transdermal or oralroutes. Further, the medication may be administered in combination withother medications. The patient may be a human or a non-human mammal.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

The invention will be described in conjunction with the followingfigures in which like reference numerals designate like elements andwherein:

FIG. 1 is a coronal view of a magnetic resonance image (MRI) scan of apatient's arthritic knee prior to routine administration of aphosphodiesterase inhibitor.

FIG. 2 is a coronal view of an MRI of the same patient's knee as in FIG.1, after routine administration of a phosphodiesterase inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of treating bone pain byadministering to a patient an effective amount of a pharmaceuticallyacceptable bone edema medication. In accordance with the presentinvention, bone edema medications, including vasoactive medications andphosphodiesterase inhibitors, are administered to a patient sufferingfrom pain, e.g. joint pain from osteoarthritis. Bone edema medicationsof the present invention reduce or eliminate intraosseous hypertensionin the bone, within the vicinity of the affected joint, by alteringvascular profusion (blood flow in and out of the bone), thereby reducingbone edema. By reducing or eliminating intraosseous hypertension, themethod of the present invention reduces or eliminates a source of painfor osteoarthritis sufferers.

Phosphodiesterases (PDE) are a diverse family of enzymes that hydrolyzecyclic nucleotides and thus play a key role in regulating intracellularlevels of second messangers—adenosine monophosphate (cAMP) and guanosinemonophosphate (cGMP)—and hence cell function. (Boswell-Smith et al.2006). PDE activity is found in every cell in the body, although thereis distinct cellular and subcellular distribution of eleven isoenzymes,which has provided many possibilities for selective therapeutic targets.Isoenzyme selective targets have been identified for specific diseases.For example, the subtype 3 phosphodiesterase enzyme PDE-3 selectiveinhibitors have been used to treat cardiovascular disease, asthma,congestive heart failure, to relax vascular and airway smooth muscle,inhibit platelet aggregation, and induce lipolysis. (Boswell-Smith etal. 2006). PDE-4, a cAMP-specific PDE, is the predominant isoenzyme inthe majority of inflammatory cells, with the exception of platelets,implicated in inflammatory airways disease. There is a currentresurgence underway in the development of PDE-4 inhibitors to treatcentral nervous system indications such as memory enhancement. The PDE-5enzyme catalyzes the breakdown of the smooth muscle relaxing agent cGMP(U.S. Pat. No. 7,091,207) making it a cGMP-specific PDE. Those ofordinary skill in the art will recognize that many compounds exist whichare inhibitors of PDE-5 including, sildenafil (marketed as Viagra®),vardenafil (marketed as Levitra®), tadalafil (marketed as Cialis®),ananafil, udenafil, zaprinast, and the like.

The inventor has discovered that exposure to a PDE-5 inhibitor reducesor eliminates the pain associated with osteoarthritis. Accordingly, inone embodiment of the present invention, the PDE-5 inhibitor that isemployed in the practice of the present invention is sildenafil(Viagra®). Sildenfil is the first oral agent approved for treatment oferectile function in men. (U.S. Pat. No. 7,091,207). Its method ofaction is understood to be as follows: Sexual stimulation results in therelease of nitric oxide from nerves and endothelial cells in the corpuscavernosum of the penis, which in turn stimulates guanylate cyclase withsubsequent formation of cGMP. Accumulation of cGMP leads to smoothmuscle cell relaxation in the arteries, arterioles and sinusoids in thecorpus cavemosum, allowing this erectile tissue to fill with blood andcausing erection. Men with erectile dysfunction may be unable tomaintain adequate amounts of cGMP because it is broken down by PDE-5,which is found in high levels in the genetalia. By inhibiting PDE-5,sildenafil allows an increase in cGMP concentration and improvedvasodilation, thus facilitating erection.

Without being bound by theory, in the practice of the present invention,the vasodilatory action of PDE-5 inhibitors such as sildenafil mayfunction by affecting the muscle tone of blood vessels, thereby alteringblood flow. By modulating the blood flow to bone of a patient sufferingfrom joint pain with a PDE-5 inhibitor, the intraosseous pressureresulting from the buildup of bone edema will be alleviated, therebypalliating joint pain.

In other embodiments of the invention, the PDE-5 inhibitors arevardenafil and tadalafil, which are also used for treatment of erectiledysfunction in men. However, the present invention is not limited tophosphodiesterase inhibitors specifically recited herein but alsoincludes other phosphodiesterase inhibitors and vasoactive medicationswhich cause alterations in the inflow and outflow of blood to bone. Thebroad concept of the present invention includes the administration ofany bone edema medication which reduces or eliminates intraosseoushypertension, including those not yet discovered, such as, but notlimited to, injectable dosage forms and solid dosage forms such astablets, capsules, and the like.

The medications used in the practice of the present invention may beadministered as a pharmaceutical preparation comprising apharmaceutically acceptable carrier. Such a pharmaceutical preparationmay be in any of many forms known to be suitable for administration ofdrugs. The medications may be administered in the pure form or in apharmaceutically acceptable formulations including suitable elixirs,binders, and the like, or as pharmaceutically acceptable salts or otherderivatives (e.g., sildenafil citrate). It should be understood that thepharmaceutically acceptable formulations and salts include liquid andsolid materials conventionally utilized to prepare injectable dosageforms and solid dosage forms such as tablets and capsules. Water may beused for the preparation of injectable compositions which may alsoinclude conventional buffers and agents to render the injectablecomposition isotonic. Other potential additives include colorants,surfactants, binders and encapsulants, diluents, excipients,disintegrating agents, coatings, preservatives and the like.

Depending on the formulation, it is expected that the active agent(e.g., PDE-5 inhibitor) will comprise 1-99% of the composition andcarrier will constitute 1-99% of the composition. Such pharmaceuticalcompositions may include any suitable pharmaceutically acceptableadditives or adjuncts to the extent that they do not hinder or interferewith the desired therapeutic effect of the medication.

Those of ordinary skill in the art will recognize that the exact dosageof the medication to be administered may vary depending on factors suchas the age, gender, weight and health status of the individual patient,as well as on the precise nature of the condition being treated.Similarly, the length of duration of the treatment with the medicationwill vary from patient to patient, and will depend on the application ofthe medication. In all cases, the amount of medication to beadministered and the precise treatment protocol should be determined bya skilled practitioner such as a physician.

The preferred dosage of medication required to practice methods of thepresent invention, i.e., the quantity sufficient to carry out themethod, is about the same as or less than that which is normally ortypically administered for previously known uses or applications of themedication, i.e., PDE-5 inhibitors for treating male erectiledysfunction. For example, to elicit a reduction in pain associated withosteoarthritis, a regular dose of 50 mg or less of Viagra® is expectedto be at least temporarily effective for most patients.

The medication may be administered by any of a wide variety of meanswhich are well known to those of ordinary skill in the art including,but not limited to, intravenously, intramuscularly, orally, rectally,and the like, or by other routes including, but not limited to,transdermal, sublingual, aerosol, etc., which is suitable for theparticular means of administration.

Further, the medications of the present invention may be administeredeither alone or together with other medications in a treatment protocol.For example, a PDE-5 inhibitor may be administered either separately orin combination with other osteoarthritis drugs.

While in some embodiments, the patient that is treated by the methods ofthe present invention are human in origin, this need not be the case.Those of ordinary skill in the art will recognize that other mammals mayalso benefit from the methods of the present invention. Thus,veterinarian applications are also contemplated. Further, patientstreated with medications according to the methods of the presentinvention may be in any stage of life, e.g., new-born, adult or aging,although as previously mentioned, osteoarthritis is considered to beprimarily a disease of the elderly.

The invention will be illustrated in more detail with reference to thefollowing Example, but it should be understood that the presentinvention is not deemed to be limited thereto.

EXAMPLE

A physician, who is also the inventor of the present invention,performed an arthroscopic surgical procedure on a male patient sufferingfrom a loose cartilage body in the setting of severe arthritis in hisknee. The patient was a competitive senior tennis player and declinedknee replacement for that reason. The purpose of the procedure wasmerely to remove a loose body and abate the mechanical symptoms itcaused. Prior to the procedure, an MRI of a coronal view of thepatient's knee was taken, as shown in FIG. 1.

Approximately one year later, the patient returned to his physician forevaluation of what was believed to be an unrelated ganglion cyst on thesame knee. To evaluate this cystic mass, another MRI of a coronal viewof the patient's knee was taken, as shown in FIG. 2. The patient hadreported that over the few months prior to the second MRI but well pastthe surgical procedures, his pain from his knee arthritis hadsignificantly improved. He inquired whether the more recent MRI (FIG. 2)revealed why this was so. The patient's physician and a seniorradiologist compared the earlier MRI (FIG. 1) to the later MRI (FIG. 2),and observed that the earlier MRI (FIG. 1) showed white spots on thepatient's tibial spines, whereas the later MRI (FIG. 2) revealed thatthe white spots had dissipated or resolved. The physician and aradiologist noted that the high signal shown in the MRI of FIG. 1represents bone edema, and hence, intraosseous hypertension. Theyfurther noted that the MRI of FIG. 2, as compared with that of FIG. 1,showed a resolution of the edema, and that although the radiographs wereotherwise unchanged, the patient's symptoms were markedly reduced. Thephysician therefore concluded that the patient had intraosseoushypertension which was shown to have dissipated or have been resolved bythe time of the MRI of FIG. 2.

Upon questioning by his physician, the patient explained that the onlydifference in his medical history (including lifestyle, activity, newillness and medications) between the time of the first and second MRIswas that he started using a phosphodiesterase inhibitor. Specifically,the patient started using Viagra® (50 mg of sildenafil, once per day).There were no other changes in the interval medical history. Thephysician inferred that reduction in knee pain experienced by thepatient was the result of the dissipation of the intraosseoushypertension which, in turn, was the result of using a phosphodiesteraseinhibitor.

While the invention has been described in detail in terms of itspreferred embodiments and with reference to the above example, it willbe apparent to those skilled in the art that the invention can bepracticed with modification within the spirit and scope of the appendedclaims. Accordingly, the present invention should not be limited to theembodiments as described above, but should further include all changes,modifications and equivalents thereof within the spirit and scope of thedescription provided herein.

1. A method of treating pain comprising administering to a patient atherapeutically effective amount of a pharmaceutically acceptable boneedema medication.
 2. The method of claim 1, wherein the pain is causedby joint disease.
 3. The method of claim 2, wherein the joint disease isosteoarthritis.
 4. The method of claim 1, wherein the pharmaceuticallyacceptable bone edema medication is a vasoactive medication.
 5. Themethod of claim 1, wherein the pharmaceutically acceptable bone edemamedication is a phosphodiesterase inhibitor.
 6. The method of claim 5,wherein the phosphodiesterase inhibitor is a subtype 5 phosphodiesteraseenzyme (PDE5) selective inhibitor.
 7. The method of claim 6, wherein thePDE5 selective inhibitor is selected from the group consisting ofavanafil, sildenafil, tadalafil, udenafil, vardenafil and zaprinast. 8.The method of claim 1, wherein the step of administering is via anintramuscular route.
 9. The method of claim 1, wherein the step ofadministering is via an oral route.
 10. The method of claim 1, whereinthe step of administering is via an intravenous route.
 11. The method ofclaim 1, wherein the patient is a human.
 12. The method of claim 1,wherein the patient is a non-human mammal.
 13. The method of claim 1,wherein the therapeutically effective amount is a dose normallyadministered for known uses of the bone edema medication.
 14. The methodof claim 1, wherein 50 mg or less of the bone edema medication isadministered.
 15. A method of reducing intraosseous hypertensioncomprising administering to a patient a therapeutically effective amountof a pharmaceutically acceptable bone edema medication.